This invention relates to novel imidazo-pyridines, -pyridazines, and -triazines, pharmaceutical compositions containing the same and methods of using same in the treatment of psychiatric disorders and neurological diseases including affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing corticotropin releasing factor (CRF), including but not limited to disorders induced or facilitated by CRF.
Corticotropin releasing factor, a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provides evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for it review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist xcex1-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn, Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (xcex1-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
In view of the above, efficacious and specific antagonists of CRF are desired as potentially valuable therapeutic agents for the treatment of psychiatric disorders and neurological diseases. It is thus desirable to discover new CRF antagonists.
Accordingly, one object of the present invention is to provide novel imidazo-pyridines, -pyridazines, and -triazines, which are useful as CRF antagonists or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide a method for treating psychiatric disorders and neurological diseases comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula I: 
or pharmaceutically acceptable salt forms thereof, wherein R1, R2, R3, and R4 are defined below, are CRF antagonists.
[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A is N or Cxe2x80x94R7;
B is N or Cxe2x80x94R8;
D is an aryl or heteroaryl group attached through an unsaturated carbon atom;
X is selected from the group CHxe2x80x94R9, Nxe2x80x94R10, O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-4 alkoxy-C1-4 alkyl, xe2x80x94SO2xe2x80x94C1-10 alkyl, xe2x80x94SO2xe2x80x94R1a, and xe2x80x94SO2xe2x80x94R1b;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94CONR13aR16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94, and wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b;
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-4 alkoxy-C1-4 alkyl, and C3-8 cycloalkyl which is substitute d with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R1c is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR13a, SH, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94OC(O)R14b, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94NR13aR16a, and xe2x80x94CONR13aR16a and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b and wherein any sulfur atom is optionally monooxidized or dioxidized;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl, xe2x80x94(CH2)1-4-heteroaryl, or xe2x80x94(CH2)1-4-heterocycle, wherein the aryl, heteroaryl, or heterocycle group is substituted or unsubstituted;
R2 is selected from the group C1-4 alkyl, C3-8 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-3 substituents selected from the group xe2x80x94CN, hydroxy, halo and C1-4 alkoxy;
alternatively R2, in the case where X is a bond, is selected from the group xe2x80x94CN, CF3 and C2F5;
R7 and R8 are independently selected at each occurrence from the group H, Br, Cl , F, I, xe2x80x94CN, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, (C1-4 alkyl)2amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C1-7 alkyl, C3-8 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkyl sulfinyl, C1-4 alkylsulfonyl, C1-6 alkylamino and (C1-4 alkyl)2amino;
R9 and R10 are independently selected at each occurrence from the group H, C1-4 alkyl, C3-6 cycloalkyl-C1-4 alkyl and C3-8 cycloalkyl;
R13 is selected from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl(C1-4 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl(C1-4 alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy C1-4 haloalkoxy, and dimethylamino;
R14a is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R14b is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17 is selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, C1-4 haloalkyl, R14S(O)nxe2x80x94C-1-4 alkyl, and R17bR19bNxe2x80x94C2-4 alkyl;
R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
alternatively, in an NR17bR19b moiety, R17b and R19b taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, methylenedioxy, C1-4 alkoxy-C1-4 alkoxy, xe2x80x94OR17, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94NO2, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CONR17R19, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C1-3 alkyl, C1-3 alkoxy, Br, Cl, F, I, xe2x80x94CN, dimethylamino, CF3, C2F5, OCF3, SO2Me and acetyl;
heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CONR17R19, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a; and,
provided that when D is imidazole or triazole, R1 is other than unsubstituted C1-6 linear or branched alkyl or C3-6 cycloalkyl.
[2] In a preferred embodiment, the present invention provides a novel compound of formula Ia: 
[3] In another preferred embodiment, the present invention provides a novel compound of formula Ib: 
[4] In another preferred embodiment, the present invention provides a novel compound of formula Ic: 
[5] In another preferred embodiment, the present invention provides a novel compound of formula Id: 
[5a] In a more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
X is selected from the group O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-8 cycloalkyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF2CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, CF3, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl or xe2x80x94(CH2)1-4-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;
R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group xe2x80x94CN, OH, Cl, F, and C1-4 alkoxy;
R7 and R8 are independently selected from the group H, Br, Cl, F, xe2x80x94CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2-amino;
R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;
R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl (C1-2 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, xe2x80x94OR17, Br, Cl , F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94NR15COR17, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19; and,
heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[5b] In an even more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
X is selected from the group O, S and a bond
R1 is substituted C1-6 alkyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94ON, xe2x80x94CO2R13a, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl which is substituted with 0-1 CH3 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl or xe2x80x94(CH2)1-4-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;
R2 is selected from the group CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R7 and R8 are independently selected from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, CCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is independently selected at each occurence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3.
[5c] In a still more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
R1 is substituted C1;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94CO2CH3, and xe2x80x94CO2CH2CH3;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, CH3-cyclopropyl, cyclobutyl, CH3-cyclobutyl, cyclopentyl, CH3-cyclopentyl;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl or xe2x80x94(CH2)1-4-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;
R2 is selected from the group CH3, CH2CH3, and CH(CH3)2;
R7 and R8 are independently selected from the group H and CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2.
[5d] In a further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
R1 is substituted (cyclopropyl)-C1 alkyl or (cyclobutyl)-C1 alkyl;
R1 is substituted with 0-1 xe2x80x94CN;
R1 is also substituted with 0-1 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3.
[5e] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)-C1 alkyl substituted with 1 substituent independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, Cl, F, and CF3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, and isoxazolyl, each heteroaryl being substituted on 0-2 carbon atoms with a substituent independently selected at each occurrence from the group CH3, OCH3, Cl, F, and CF3.
[5f] In an even further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
R1 is selected from the group
R1 is selected from the group (cyclopropyl)CHxe2x80x94CH3, (cyclopropyl)CHxe2x80x94CH2CH3, (cyclopropyl)CHxe2x80x94CH2OCH3, (cyclopropyl)CHxe2x80x94CH2CH2CH3, (cyclopropyl)CHxe2x80x94CH2CH2OCH3, (cyclopropyl)2CH, phenyl(cyclopropyl)CH, furanyl(cyclopropyl)CH, thienyl(cyclopropyl)CH, isoxazolyl(cyclopropyl)CH, (CH3-furanyl)(cyclopropyl)CH, (cyclobutyl)CHxe2x80x94CH3, (cyclobutyl)CHxe2x80x94CH2CH3, (cyclobutyl)CHxe2x80x94CH2OCH3, (cyclobutyl)CHxe2x80x94CH2CH2CH3, (cyclobutyl)CHxe2x80x94CH2CH2OCH3, (cyclobutyl)2CH, phenyl(cyclobutyl)CH, furanyl(cyclobutyl)CH, thienyl(cyclobutyl)CH, isoxazolyl(cyclobutyl)CH, and (CH3-furanyl)(cyclobutyl)CH;
[5g] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[5h] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[5i] In another preferred embodiment, the present invention provides a novel compound of formula Id, wherein the compound is selected from the group:
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-c]pyridine;
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridine;
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridine;
4-(2,4-Dichlorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridine;
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridine;
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridine;
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridine;
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridine;
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridine;
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridine;
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridine;
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridine;
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridine;
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazine;
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]pyridazine;
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]pyridazine;
4-(2,4-Dichlorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]pyridazine;
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]pyridazine;
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]pyridazine;
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]pyridazine;
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]pyridazine;
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]pyridazine;
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]pyridazine;
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]pyridazine;
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]pyridazine;
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]pyridazine;
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-c]pyridazine;
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridazine;
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridazine;
4-(2,4-Dichlorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridazine;
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridazine;
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridazine;
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridazine;
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridazine;
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridazine;
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridazine;
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyridazine;
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c]pyridazine;
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyridazine;
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]triazine;
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]triazine;
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]triazine;
4-(2,4-Dichlorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]triazine;
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]triazine;
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]triazine;
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]triazine;
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]triazine;
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]triazine;
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]triazine;
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-d]triazine;
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d]triazine; and,
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]triazine;
or a pharmaceutically acceptable salt form thereof.
[5j] In another more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
R1 is C3-8 cycloalkyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94CONR13aR16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C4-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94, and wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b; and,
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, C1-2 alkoxy-C1-2 alkyl, and xe2x80x94NR13aR16a.
[5k] In another even more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
X is selected from the group O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group cyclopropyl, cyclobutyl, and cyclopentyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, and C4-8 cycloalkyl, wherein one carbon atom in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl , F, CF3, CF2CF3, xe2x80x94OR13a, C1-2 alkoxy-C1-2 alkyl, and xe2x80x94NR13aR16a;
R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl , F, CF3, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group xe2x80x94CN, OH, Cl , F, and C1-4 alkoxy;
R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;
R7 and R8 are independently selected from the group H, Br, Cl, F, xe2x80x94CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2-amino;
R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, xe2x80x94OR17, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94NR15COR17, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19; and,
heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[5l] In another still more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
X is selected from the group O, S and a bond
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94CO2R13a, and C4-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF3, xe2x80x94OR13a, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, and xe2x80x94NR13aR16a;
R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R7 and R8 are independently selected from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is independently selected at each occurence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3.
[5m] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
R1 is substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, and CF3;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, and CH(CH3)2;
R7 and R8 are independently selected from the group H and CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2.
[5n] In another even further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
R1 is substituted with 0-2 substituents independently selected at each occurrence from the group R1a, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, and CF3; and,
R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3.
[5o] In a still further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[5p] In another still further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[5q] In another more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
R1 is selected from the group C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 alkoxy-C1-4 alkyl;
R1 is substituted with a C3-8 cycloalkyl group, wherein 0-1 carbon atoms in the C4-8 cycloalkyl group is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94;
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b; and,
R1c is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR13a, SH, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94OC(O)R14b, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94NR13aR16a, and xe2x80x94CONR13aR16a and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b and wherein any sulfur atom is optionally monooxidized or dioxidized.
[5r] In another even more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
X is selected from the group O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-8 cycloalkyl;
R1 is substituted with a C3-6 cycloalkyl group, wherein 0-1 carbon atoms in the C4-6 cycloalkyl group is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF2CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group CO1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, CF3, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group xe2x80x94CN, OH, Cl, F, and C1-4 alkoxy;
R7 and R8 are independently selected from the group H, Br, Cl, F, xe2x80x94CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2-amino;
R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;
R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl (C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, xe2x80x94OR17, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94NR15COR17, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19; and,
heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[5s] In another still more preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
X is selected from the group O, S and a bond
R1 is C1-6 alkyl;
R1 is substituted with a C3-6 cycloalkyl, wherein one carbon atom in the C4-6 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, and C3-6 cycloalkyl which is substituted with 0-1 CH3 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R7 and R8 are independently selected from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is independently selected at each occurence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3.
[5t] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)C1 alkyl;
R1 is substituted with 1-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, CH3-cyclopropyl, cyclobutyl, CH3-cyclobutyl, cyclopentyl, CH3-cyclopentyl;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, and CH(CH3)2;
R7 and R8 are independently selected from the group H and CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2.
[5u] In another even further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)C1 alkyl;
R1 is substituted with 1-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3.
[5v] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[5w] In another further preferred embodiment, the present invention provides a novel compound of formula Id, wherein:
D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[6] In a second embodiment, the present invention provides a novel method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals, comprising: administering to the mammal a therapeutically effective amount of a compound of formula (I): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A is N or Cxe2x80x94R7;
B is N or Cxe2x80x94R8;
D is an aryl or heteroaryl group attached through an unsaturated carbon atom;
X is selected from the group CHxe2x80x94R9, Nxe2x80x94R10, O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-4 alkoxy-C1-4 alkyl, xe2x80x94SO2xe2x80x94C1-10 alkyl, xe2x80x94SO2xe2x80x94R1a, and xe2x80x94SO2xe2x80x94R1b;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94CONR13aR16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94, and wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b;
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-4 alkoxy-C1-4 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
R1a is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R1c is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR13a, SH, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94OC(O)R14b, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94NR13aR16a, and xe2x80x94CONR13aR16a and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b and wherein any sulfur atom is optionally monooxidized or dioxidized;
R2 is selected from the group C1-4 alkyl, C3-8 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-3 substituents selected from the group xe2x80x94CN, hydroxy, halo and C1-4 alkoxy;
alternatively R2, in the case where X is a bond, is selected from the group xe2x80x94CN, CF3 and C2F5;
R7 and R8 are independently selected at each occurrence from the group H, Br, Cl, F, I, xe2x80x94CN, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, (C1-4 alkyl)2amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C1-7 alkyl, C3-8 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkyl sulfinyl, C1-4 alkylsulfonyl, C1-6 alkylamino and (C1-4 alkyl)2amino;
R9 and R10 are independently selected at each occurrence from the group H, C1-4 alkyl, C3-6 cycloalkyl-C1-4 alkyl and C3-8 cycloalkyl;
R13 is selected from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl (C1-4 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl(C1-4 alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy C1-4 haloalkoxy, and dimethylamino;
R14a is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R14b is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17 is selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, C1-4 haloalkyl, R14S(O)nxe2x80x94C1-4 alkyl, and R17bR19bNxe2x80x94C2-4 alkyl;
R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
alternatively, in an NR17bR19b moiety, R17b and R19b taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, methylenedioxy, C1-4 alkoxy-C1-4 alkoxy, xe2x80x94OR17, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94NO2, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CONR17R19, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C1-3 alkyl, C1-3 alkoxy, Br, Cl, F, I, xe2x80x94CN, dimethylamino, CF3, C2F5, OCF3, SO2Me and acetyl; and,
heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CONR17R19, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[7] In a third embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A is N or Cxe2x80x94R7;
B is N or Cxe2x80x94R8;
D is an aryl or heteroaryl group attached through an unsaturated carbon atom;
X is selected from the group CHxe2x80x94R9, Nxe2x80x94R10, O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-4 alkoxy-C1-4 alkyl, xe2x80x94SO2xe2x80x94C1-10 alkyl, xe2x80x94SO2xe2x80x94R1a, and xe2x80x94S2xe2x80x94R1b;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94CONR13aR16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13a, NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94, and wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b;
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-4 alkoxy-C1-4 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
R1a is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R1c is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR13a, SH, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94OC(O)R14b, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94NR13aR16a, and xe2x80x94CONR13aR16a and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b and wherein any sulfur atom is optionally monooxidized or dioxidized;
R2 is selected from the group C1-4 alkyl, C3-8 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-3 substituents selected from the group xe2x80x94CN, hydroxy, halo and C1-4 alkoxy;
alternatively R2, in the case where X is a bond, is selected from the group xe2x80x94CN, CF3 and C2F5;
R7 and R8 are independently selected at each occurrence from the group H, Br, Cl, F, I, xe2x80x94CN, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, (C1-4 alkyl)2amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C1-7 alkyl, C3-8 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkyl sulfinyl, C1-4 alkylsulfonyl, C1-6 alkylamino and (C1-4 alkyl)2amino;
R9 and R10 are independently selected at each occurrence from the group H, C1-4 alkyl, C3-6 cycloalkyl-C1-4 alkyl and C3-8 cycloalkyl;
R13 is selected from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl(C1-4 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl(C1-4 alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy C1-4 haloalkoxy, and dimethylamino;
R14a is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R14b is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17 is selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, C1-4 haloalkyl, R14S(O)nxe2x80x94C1-4 alkyl, and R17bR19bNxe2x80x94C2-4 alkyl;
R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
alternatively, in an NR17bR19b moiety, R17b and R19b taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, methylenedioxy, C1-4 alkoxy-C1-4 alkoxy, xe2x80x94OR17, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94NO2, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CONR17R19, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C1-3 alkyl, C1-3 alkoxy, Br, Cl, F, I, xe2x80x94CN, dimethylamino, CF3, C2F5, OCF3, SO2Me and acetyl; and,
heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CONR17R19, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
In another preferred embodiment, R1 is other than a cyclohexyl-(CH2)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10xe2x80x94 group;
In another preferred embodiment, R1 is other than an aryl-(CH2)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10xe2x80x94 group, wherein the aryl group is substituted or unsubstituted;
In another preferred embodiment, R1 is other than a heteroaryl-(CH2)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10xe2x80x94 group, wherein the heteroaryl group is substituted or unsubstituted;
In another preferred embodiment, R1 is other than a heterocyclyl-(CH2)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10xe2x80x94 group, wherein the heterocyclyl group is substituted or unsubstituted;
In another preferred embodiment, when D is imidazole or triazole, R1 is other than unsubstituted C1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 linear or branched alkyl or C3, 4, 5, 6, 7, or 8 cycloalkyl.
In another preferred embodiment, R1a is not substituted with OR17.
In fourth embodiment, the present invention provides intermediate compounds useful in preparation of the CRF antagonist compounds and processes for making those intermediates, as described in the following description and claims.
In a fifth embodiment, the present invention provides CRF antagonist compounds and labelled derivatives thereof as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounter-ionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7-to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemsxe2x80x9d is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a all stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic agent.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference.
The following abbreviations are used herein:
AcOH acetic acid
t-BuOK potassium tert-butoxide
DEAD diethyl azodicarboxylate
DMSO dimethyl sulfoxide
EtOAcethyl acetate
EtOH ethanol
NaHMDS sodium bis(trimethylsilyl)amide
PPh3 triphenylphosphine
THF tetrahydrofuran
TLC thin layer chromatography 
The compounds of this invention of formula (Ia) may be prepared using the methods shown in Scheme 1. In this procedure the 5-chloro-3,4-diaminopyridazine precursor may be cyclized to the desired imidazopyridiazines using orthoesters (for R2xe2x80x94Xxe2x80x94=H, alkyl, alkoxy, etc.), orthocarbonates, carboxylic acids, carboxylic acid esters, alkyl imidates and other reagents appropriate to the product desired, and reaction conditions known to those skilled in the art of organic synthesis. The synthesis of the starting material where R8=H, and the chemistry thereof has been described by Kurashi and Castle (J. Het. Chem. 1964, 1, 42).
The imidazolepyridazine may then be N-alkylated using, for example, base promoted conditions (e.g., NaHMDS/R1-LG, where LG=halide, sulfonate, or other appropriate leaving group) or Mitsunobu reaction conditions (e.g., DEAD/PPh3/R1xe2x80x94OH). The compounds of formula (Ia) are then formed by cross coupling with an appropriate arylboronic acid, arylstannane, or arylzinc reagent under known conditions. In the case where R1 is a protecting group such as benzyl, p-methoxybenzyl, or tetrahydropyranyl (J. Het. Chem. 1968, 5, 13), the group may be removed and N-alkylation at this point gives compounds of formula (Ia). 
Compounds of formula (Ia) may also be prepared via the method outlined in Scheme 2. Commercially available 4,5-dibromo-pyridazin-3-one is N and/or O benzylated then cross coupled in, for example, a Suzuki reaction (D-B(OH)2/Pd(PPh3)4/Na2CO3) followed by deprotection. Chlorination using, for example, POCl3 gives a chloro-pyridazine which may then be reacted for example, with an amidine. N-alkylation of the resulting bicyclic compound using the methods described above affords the desired compounds of formula (Ia).
Compounds of formula (Ia) may also be prepared via the method outlined in Scheme 2b. In this procedure, a 2-chloroacetophenone is condensed with a dialkyl malonate (e.g., TiCl4/CCl4/pyridine/THF) or nitroacetate. The product from this reaction is treated with hydrazine to give an intermediate which is oxidized using, for example, DDQ or NBS to give the pyridazinone intermediate. Chlorination (or bromination) using POCl3 (or POBr3) affords a chloro- (or bromo-) pyridazine intermediate.
This intermediate, where Y=ester in Scheme 2b, may now be converted to the acid (e.g., LiOH/H2O/MeOH/THF) and then subjected to conditions such as the Curtius reaction or modifications thereof (e.g., DPPA, Et3N, t-BuOH; TFA/CH2Cl2), which transform the acid to an amino group. Substitution of the halide with an appropriate amine using, for example, nucleophilic substitution or cross-coupling reactions, affords an intermediate which can then be converted to the desired imidazopyridiazines (Ia) by cyclization using orthoesters (for R2xe2x80x94Xxe2x80x94=H, alkyl, alkoxy, etc.), orthocarbonates, carboxylic acids, carboxylic acid esters, alkyl imidates and other reagents appropriate to the product desired, and reaction conditions known to those skilled in the art of organic synthesis. 
The intermediate where Y=NO2 in Scheme 2b may be treated with an appropriate amine using, for example, nucleophilic substitution conditions. Reduction of the nitro group to the amine (e.g., Fe/AcOH or sodium dithionite/water/EtOH) affords an intermediate which can then be converted to the desired imidazopyridiazines (Ia) by cyclization using orthoesters (for R2xe2x80x94Xxe2x80x94=H, alkyl, alkoxy, etc.), orthocarbonates, carboxylic acids, carboxylic acid esters, alkyl imidates and other reagents appropriate to the product desired, and reaction conditions known to those skilled in the art of organic synthesis. 
The compounds of this invention of formula (Id) may be prepared using the methods shown in Scheme 3. In this procedure, the 3,4-diamino-5-nitropyridine precursor may be cyclized to the desired imidazopyridines using orthoesters (for R2xe2x80x94Xxe2x80x94=H, alkyl, alkoxy, etc.), orthocarbonates, carboxylic acids, carboxylic acid esters, alkyl imidates and other reagents appropriate to the product desired, and reaction conditions known to those skilled in the art of organic synthesis. The synthesis of the precursor where R7 and R8=H, and the chemistry thereof has been described by Graboyes and Day (J. Am. Chem. Soc. 1957, 79, 6421). Reduction of the nitro group using, for example, stannous chloride, provides the amino compound. Conversion of the amino group to a chloride, bromide or iodide may now be effected via diazotization of the amine followed by displacement with halogen anion. The halide compounds may then be N-alkylated using, for example, base promoted conditions (e.g., NaHMDS/R1-LG, where LG=halide, sulfonate, or other appropriate leaving group) or Mitsunobu reaction conditions (e.g., DEAD/PPh3/R1xe2x80x94OH). Cross coupling with an appropriate arylboronic acid, arylstannane, or arylzinc reagent under known conditions to yield compounds of formula (Id). In the case where R1 is a protecting group, the group may now be removed and N-alkylation at this point gives compounds of formula (Id). 
Compounds of Formula (Ib) may be prepared, using the procedures outlined in Scheme 4. The starting material (where Ra is lower alkyl, X and R2 are defined above) may be treated with a compound of the formula Dxe2x80x94M (where M=Li, Na, MgBr, MgCl, ZnCl, CeC2 and D is defined above) in the presence of an inert solvent at reaction temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. to provide the keto-imidazole. Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) or aromatic hydrocarbons (preferably benzene or toluene).
The imidazolepyridazine can then be formed by reaction with hydrazine in an inert solvent. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from xe2x88x9280 to 120xc2x0 C.
The hydroxypyridazine may then be treated with a halogenating agent to give halo derivatives which may be isolated or prepared in situ. Halogenating agents include, but are not limited to, SOCl2, POCl3, PCl3, PCl5, POBr3, PBr3 or PBr5. These intermediates may be treated with a compound of the Formula R7H in the presence or absence of a base in an inert solvent. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), aromatic amines (preferably pyridine) or alkyl-lithiums in the presence or absence of salts or complexes of Cu, Ce, Mg, Pd, Ni, Zn, Sn. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from xe2x88x9220 to 100xc2x0 C.
The resulting compounds may then be reacted with an alkylating agent of the Formula R1X (where R1 is defined above) and X is halo, alkanesulfonyloxy, arylsulfonyloxy or haloalkane-sulfonyloxy) in the presence or absence of a base in an inert solvent to provide compounds of Formula (Id). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), aromatic amines (preferably pyridine) or alkyl-lithiums in the presence or absence of salts or complexes of Cu, Ce, Mg, Pd, Ni, Zn, Sn. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from xe2x88x9220 to 100xc2x0 C.
Alternatively, alkylation to compounds of Formula (Ib) by treatment with a azodicarboxylate ester RbO2CNxe2x95x90NCO2Rb (where Rb is a lower alkyl group) and a compound of the Formula R1OH in the presence of a triarylphosphine (where aryl is phenyl or furyl, each optionally substituted by 0 to 3 alkyl groups) in an inert solvent. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from xe2x88x9220 to 100xc2x0 C. 
Compounds of Formula (Ib) may also be prepared, using the procedures outlined in Scheme 5. The starting diester may be treated with a reducing agent in inert solvent to afford an aldehyde. Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane, dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides, or dialkyl aluminum hydrides (such as di-isobutylaluminum hydride). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from xe2x88x9280 to 100xc2x0 C.
Alternatively, the aldehyde may be prepared by a two step sequence: treatment with a reducing agent in an inert solvent, followed by treatment with an oxidizing agent in an inert solvent. Reducing agents and inert solvents are defined above. Oxidizing agents include, but are not limited to, combinations of oxalyl chloride, dimethyl sulfoxide and organic bases, MnO2, KMnO4, pyridinium dichromate, pyridinium chlorochromate or combinations of SO3 and organic bases. Organic bases include, but are not limited to, trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine).
The aldehyde may then be reacted with hydrazine in an inert solvent to form an imidazole. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from xe2x88x9280 to 120xc2x0 C.
The hydroxy group may then be treated with sulfonylating agents in the presence or absence of a base to give alkanesulfonyloxy, arylsulfonyloxy or haloalkylsulfonyloxy derivatives, which may be isolated or used in situ. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).
The sulfonylated intermediates may then be reacted with compounds of the formula Dxe2x80x94B(OH)2 in the presence of salts or complexes of Pd, Ni, or Sn, in the presence or absence of a base in an inert solvent to provide compounds of Formula (Ib). Bases may include, but are not limited to, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloroethane). 
Compounds of Formula (Ib) may also be prepared by the procedures outlined in Scheme 6. The starting imidazoles may treated with halogenating agents in an inert solvent to provide a dihalo-imidazole. Halogenating agents include, but are not limited to, SOCl2, POCl3, PCl3, PCl5, POBr3, PBr3 or PBr5. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).
One halogen may be replaced via treatment with a compound of Formula RcM (where Rc is lower alkyl and M may be Li, Na, MgBr, MgCl, ZnCl, CeCl2) in an inert solvent, followed by reaction with a compound of Formula R7xe2x80x94(Cxe2x95x90O)xe2x80x94Y (where R7 is defined above and Y is halogen, lower alkoxy, lower alkanoyloxy or (RdO)2(Pxe2x95x90O)O (where Rd is lower alkyl or phenyl)). The acyl compounds my be protected by reaction with acetal- or ketal-forming reagents (where Rd or Re are each lower alkyl, or taken together they form a lower alkylene chain). These acetal- or ketal-forming reagents may be combinations of lower alkyl alcohols or diols and acids or trialkylorthoformates and acids. Such acids may be present in catalytic or stoichiometric amounts. Such acids include, but are not limited to, alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably glyme or diglyme), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halocarbons of 1 to 10 carbons and 1 to 10 halogens (preferably chloroform). Preferred reaction temperatures range from ambient temperature to 150xc2x0 C.
Moiety D may be attached by treatment with a compound of Formula RcM (where Rc is lower alkyl and M may be Li, Na, MgBr, MgCl, ZnCl, CeCl2) in an inert solvent, followed by reaction with a compound of Formula Dxe2x80x94(Cxe2x95x90O)xe2x80x94Y (where D is defined above and Y is halogen, lower alkoxy, lower alkanoyloxy or (RdO)2(Pxe2x95x90O)O (where Rd is lower alkyl or phenyl)). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or aromatic hydrocarbons (preferably benzene or toluene).
Compounds of Formula (Ib) may finally be prepared by (a) hydrolysis with an acid, followed by (b) reaction with hydrazine in an inert solvent. Acids include, but are not limited to, alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably glyme or diglyme), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halocarbons of 1 to 10 carbons and 1 to 10 halogens (preferably chloroform). Preferred reaction temperatures for steps (a) or (b) range from ambient temperature to 150xc2x0 C.
If intermediates contain functional groups which are sensitive to the reaction conditions employed, these groups may be protected using methods known to those skilled in the art. These methods include, but are not limited to, those described in Protective Groups in Organic Synthesis (Greene, Wuts; 2nd ed., 1991, John Wiley and Sons, Inc.).